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Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

ABSTRACT: To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.Human LDL was isolated and modified by MG in vitro to minimal extent (MG(min)-LDL) as occurs in vivo. Atherogenic characteristics of MG(min)-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor-binding, and aortal deposition. The major site of modification of apolipoprotein B100 (apoB100) modification was investigated by mass spectrometric peptide mapping.MG(min)-LDL contained 1.6 molar equivalents of MG modification-mostly hydroimidazolone-as found in vivo. MG(min)-LDL had decreased particle size, increased binding to proteoglycans, and increased aggregation in vitro. Cell culture studies showed that MG(min)-LDL was bound by the LDL receptor but not by the scavenger receptor and had increased binding affinity for cell surface heparan sulfate-containing proteoglycan. Radiotracer studies in rats showed that MG(min)-LDL had a similar fractional clearance rate in plasma to unmodified LDL but increased partitioning onto the aortal wall. Mass spectrometry peptide mapping identified arginine-18 as the hotspot site of apoB100 modification in MG(min)-LDL. A computed structural model predicted that MG modification of apoB100 induces distortion, increasing exposure of the N-terminal proteoglycan-binding domain on the surface of LDL. This likely mediates particle remodeling and increases proteoglycan binding.MG modification of LDL forms small, dense LDL with increased atherogenicity that provides a new route to atherogenic LDL and may explain the escalation of cardiovascular risk in diabetes and the cardioprotective effect of metformin.

SUBMITTER: Rabbani N

PROVIDER: S-EPMC3121424 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

Rabbani Naila N Godfrey Lisa L Xue Mingzhan M Shaheen Fozia F Geoffrion Michèle M Milne Ross R Thornalley Paul J PJ

Diabetes 20110526 7

<h4>Objective</h4>To study whether modification of LDL by methylglyoxal (MG), a potent arginine-directed glycating agent that is increased in diabetes, is associated with increased atherogenicity.<h4>Research design and methods</h4>Human LDL was isolated and modified by MG in vitro to minimal extent (MG(min)-LDL) as occurs in vivo. Atherogenic characteristics of MG(min)-LDL were characterized: particle size, proteoglycan-binding, susceptibility to aggregation, LDL and non-LDL receptor-binding, a ...[more]

PMID: 21617182

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Project description:Current pre-clinical evidences of Centella focus on its pharmacological effects on normal wound healing but there are limited studies on the bioactivity of Centella in cellular dysfunction associated with diabetic wounds. Hence we planned to examine the potential of Centella cordifolia in inhibiting methylglyoxal (MGO)-induced extracellular matrix (ECM) glycation and promoting the related cellular functions. A Cell-ECM adhesion assay examined the ECM glycation induced by MGO. Different cell types that contribute to the healing process (fibroblasts, keratinocytes and endothelial cells) were evaluated for their ability to adhere to the glycated ECM. Methanolic extract of Centella species was prepared and partitioned to yield different solvent fractions which were further analysed by high performance liquid chromatography equipped with photodiode array detector (HPLC-PDA) method. Based on the antioxidant [2,2-diphenyl-1-picrylhydrazyl (DPPH) assay] screening, anti-glycation activity and total phenolic content (TPC) of the different Centella species and fractions, the ethyl acetate fraction of C. cordifolia was selected for further investigating its ability to inhibit MGO-induced ECM glycation and promote cellular distribution and adhesion. Out of the three Centella species (C. asiatica, C. cordifolia and C. erecta), the methanolic extract of C. cordifolia showed maximum inhibition of Advanced glycation end products (AGE) fluorescence (20.20 ± 4.69 %, 25.00 ± 3.58 % and 16.18 ± 1.40 %, respectively). Its ethyl acetate fraction was enriched with phenolic compounds (3.91 ± 0.12 mg CAE/?g fraction) and showed strong antioxidant (59.95 ± 7.18 ?M TE/?g fraction) and antiglycation activities. Improvement of cells spreading and adhesion of endothelial cells, fibroblasts and keratinocytes was observed for ethyl acetate treated MGO-glycated extracellular matrix. Significant reduction in attachment capacity of EA.hy926 cells seeded on MGO-glycated fibronectin (41.2%) and attachment reduction of NIH3t3 and HaCaT cells seeded on MGO-glycated collagen (33.7% and 24.1%, respectively) were observed. Our findings demonstrate that ethyl acetate fraction of C. cordifolia was effective in attenuating MGO-induced glycation and cellular dysfunction in the in-vitro wound healing models suggesting that C. cordifolia could be a potential candidate for diabetic wound healing. It could be subjected for further isolation of new phytoconstituents having potential diabetic wound healing properties.

Dataset Information

Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

Publications

Glycation of LDL by methylglyoxal increases arterial atherogenicity: a possible contributor to increased risk of cardiovascular disease in diabetes.

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